Table 1.

Preclinical targeted therapy–based combination treatments in ARMS and ERMS

CategoryTarget(s)CombinationaSubtypes includedIn vivoEffect combination/effect monotherapyRef.
RTKs
IGF1RIGFR + ALKR1507 + TAE684ARMS ERMSNoCI ≤ 1.0 in ARMS (Rh41, Rh30) cell lines(6)
ALK (IGF1R) + multi-kinaseCeritinib + sorafenibARMS ERMSNoCI < 1.0 in ERMS (RD) and ARMS (Rh30) cell lines (ceritinib + ≥10 μmol/L sorafenib)(8)
ALK (IGF1R) + SrcCeritinib + dasatinibARMS ERMSNoCI < 1.0 in ARMS (Rh41, Rh30) and ERMS (RD, Rh18) cell lines(9)
IGF1R or IR/IGF1R + YESMK0646 + AZD0530ARMSYesIn vitro: Increased apoptosis(10)
BMS754807 + AZD0530ERMSIn vivo: Increased tumor reduction
R1507 + AZD0530
R1507 + dasatinibb
IGF1R + PDGFRβR1507 + pazopanibARMSYescIn vitro: Re-sensitization to anti-IGF1R treatment(11)
R1507 + crenolanibbERMSIn vivo: Slight increased delay tumor growth, no complete regression
R1507 + imatinib
IGF1R + PI3K or mTORC1/2R1507 + recombinant IGFBP2ARMSNoRe-sensitization to anti-IGF1R treatment(12)
R1507 + buparlisib
R1507 + Ku-0063794
VEGFRVEGF(R) + chemotherapyBevacizumab + namitecanERMSYesIn vivo: Low dose namitecan enhanced tumor growth reduction(18)
Sunitinib + namitecan
Heparanase + VEGF(R)SST0001 + bevacizumabARMSNoReduced angiogenic factor expression(19)
SST0001 + sunitinibERMSReduced cellular invasion
EGFREGFR + chemotherapyCetuximab + dactinomycinARMS ERMSNoCI < 1.0 in ARMS (Rh30) and ERMS (RD) cell lines with increased apoptosis(22)
EGFR (drug conjugate)EGFR-conjugated immunotoxin (exotoxin A)ERMSNoN.A.(23)
EGFR (drug conjugate)EGFR-conjugated immunotoxin (human granzyme B) (+chloroquine)ERMSNoN.A. (chloroquine increased potency)(24)
FGFRFGFR4 + IGF1RBGJ398 + AEW541ARMSNoCI < 1.0 in ARMS (RMS13) cell line(29)
PDGFRαMulti-kinase + SrcImatinib + PP2(murine)NoImatinib + PP2: Enhanced cell viability reduction(31)
Sorafenib + PP2ARMSSorafenib monotherapy: Most effective in reducing cell viability. Effective in absence of PDGFRα.
Sorafenib + PP2: No added effect
Downstream signaling pathways
PI3K/AKT/mTORPI3K + IGF1R or mTOR or MEKBuparlisib + AEW541ARMSNoCI < 1.0 in ARMS (SJCRH30) and ERMS (RD) cell lines(36)
Buparlisib + rapamycinc
Buparlisib + trametinibcERMS
PI3K + MEKPI103 + U0126ARMS ERMSNoCI < 1.0 in ARMS (Rh30, RMS13) and ERMS (RD) cell lines(37)
PI3K + MEKAZD8055 + selumetinibbARMSYesIn vitro: CI < 1.0 in ARMS (Rh30) and ERMS (RD, RMS-YM) cell lines(38)
ZSTK474 + selumetinibcERMSIn vivo: AZD8055: Enhanced reduction downstream signaling
BEZ235 + selumetinibb,cIncreased toxicity
BEZ235: No added effect
RAS/MEK/ERKMEK + chymotrypsin-like serine proteasePD98059 + TPCKERMSYesdIn vitro: Increased reduction cell proliferation(44)
In vivo: Enhanced reduction tumor growth
MEKU0126 + radiotherapyARMSNoIn vitro: ERMS: Enhanced reduction sphere culture(45)
ERMSARMS: No added effect
JAK/STAT3STAT3/GP160 + MEKLY5 + doxorubicinARMSNoIncreased inhibition STAT3 activity(46)
LY5 + cisplatinIncreased reduction of cell migration
LY5 + selumetinibIncreased apoptosis
Bazedoxifine + doxorubicin
Bazedoxifine + cisplatin
Bazedoxifine + selumetinib
Hedgehog signaling
HedgehogGLI1–2 + mTORGANT61 + temsirolimusARMSNoInduction cell cycle arrest(49)
GANT61 + rapamycinERMSIncreased apoptosis
GANT61 + vincristine
GLI1-2 + PI3K/mTORGANT61 + PI103bARMSYeseIn vitro: Enhanced apoptosis with reduced downstream signaling(50)
GANT61 + BEZ235ERMSIn vivo: Decreased clonogenic survival, sphere formation and tumor growth
GANT61 + GDC0941
GANT61 + RAD001
GANT61 + AZD8055
GLI1 + chemotherapyATO + vincristineARMSNoCI < 1.0 in ARMS (Rh30) and ERMS (RD) cell lines(51)
ATO + vinblastineERMS
ATO + eribulin
GLI1 + SMOATO + itraconazoleARMS ERMSNoLimited added effects in spheroid culture(52)
GLI1 + GSK3ATO + lithium chlorideARMS ERMSNoLimited added effects in spheroid culture(53)
Apoptosis pathway
ApoptosisTRAILR1 of TRAILR2 + IAPmapatumumab + IAPi #2f(TRAILR1)ARMSNoTRAILR1: No added effect(54)
mapatumumab + IAPi #3fERMSTRAILR2: Increased reduction cell viability
lexatumumab + IAPi #2 (TRAILR2)
lexatumumab + IAPi #3
Survivin + chemotherapyYM155 + cisplatinERMSYesIn vitro/in vivo: Increased cell viability and caspase-3 activity(55)
Despite increase caspase 3 activity, no increase in apoptotic cells
mTOR + Bcl-2/BCL-xL/BCL-w or chemotherapyAZD8055 + ABT737ARMSNoABT737: CI <1.0 in ARMS (RMS13, Rh30) and ERMS (RD, TE671) cell lines(56)
AZD8055 + doxorubicinERMSChemotherapy: No added effects
AZD8055 + vincristine
AZD8055 + dactinomycin
DNA damage response (DDR)
PARP1PARP1 and/or tdp1 siRNA with or without chemotherapyRucaparib + irinotecanARMSNoPARP/tdp1 siRNA + irinotecan: Increased irinotecan sensitivity(59)
Olaparib + irinotecanERMSCombination tdp1 siRNA: Added effect on cell viability
Veliparib + irinotecan
tdp1 siRNA + irinotecan
Rucaparib + tdp1 siRNA
PARP1 + chemotherapyOlaparib + carboplatinARMSNoIrinotecan, melphalan, doxorubicin: CI < 1.0 in ARMS (SJCRH30) and ERMS (RD) cell lines(60)
Olaparib + SN38ERMSCarboplatin, vincristine: CI >0.5 and ≤1.0 in ARMS (SJCRH30) and ERMS (RD) cell lines
Olaparib + vincristine
Olaparib + melphalan
Olaparib + doxorubicin
PARP1 + chemotherapyTalazoparib + temozolomidehARMSYeskIn vitro: Temozolomide: potentiating anti-tumor effects in ARMS (Rh41, Rh30) and ERMS (RD, Rh18) cell lines(61)
Talazoparib + topotecanERMSTopotecan: No added effects
In vivo: 2/3 models showed treatment response
1/3 models showed maintained CR
Cell cycle
PLKPLK1 catalytic domain + chemotherapyBI2536 + vincristinehARMSYesIn vitro: Vincristine, vinblastine, vinorelbine: CI < 1.0 in ARMS (Rh30) and ERMS (RD) cell lines(65)
BI2536 + vinblastineERMSDoxorubicin, paclitaxel: CI > 1.0 in ARMS (Rh30) and ERMS (RD) cell lines
BI2536 + vinorelbineIn vivo: Reduced tumor growth which remained stable for 56 days
BI2536 + doxorubicin
BI2536 + paclitaxel
Volasertib + vincristineh
Volasertib + vinblastine
Volasertib + vinoelbine
Volasertib + doxorubicin
Volasertib + paclitaxel
PLK1 catalytic domain + chemotherapyVolasertib + vincristineERMSNoVincristine: CI ≤ 1.0 in ERMS (RMS-1) cell line(66)
Volasertib + etoposideEtoposide: CI > 1.0 in ERMS (RMS-1) cell line
PLK1 catalytic domain or polo-box domain + chemotherapyBI2536 + eribulinhARMSYesjCatalytic domain: In vitro: CI < 1.0 in ERMS (RD, TE381.T) CI 0.5-1 and ≥ 1 in ARMS (RMS13, Rh30) cell lines.(67)
Poloxin + vincristinelERMSIn vivo: Reduction tumor growth
Polo-box domain
In vitro: CI 0.5-1.0 and ≥ 1.0 in ERMS (RD) cell line
Wee1Wee1 + proteasome or multi-kinase or chemotherapyAZD1775 + bortezomibARMSNoCabozantinib and bortezomib: Most effective in combination with AZD1775(70)
AZD1775 + cabozantinibERMS
AZD1775 + cyclophosphamide
AZD1775 + irinotecan
AZD1775 + etoposide
AZD1775 + dactinomycin
AZD1775 + virorelbine
Wee1 + chemotherapyAZD1775 + irinotecan + vincristine(O-PDX) ARMS ERMSYeskIncreased tumor response compared to monotherapy AZD1775 or combined chemotherapy(71)
CDKCDK + IGF1RPalbociclib + BMS754807RMSpNoCI not available, synergistic effects mentioned(73)
CDK + Wee1 or chemotherapyPalbociclib + AZD1775ERMSNoAZD1775: CI < 1.0 in ERMS (RD) cell line(74)
Palbociclib + doxorubicinDoxorubicin: CI > 1.0 in ERMS (RD) cell line
Fusion proteinPAX3-FOXO1RGB-LRP-P3FoARMSYesN.A.(75)
Epigenome
Histone modificationHDAC + chemotherapyVorinostat + doxorubicinARMSNoIncreased reduction cell viability and increased apoptosis(77)
Vorinostat + etoposideERMS
Vorinostat + cyclophosphamide
Vorinostat + vincristine
HDAC + chemotherapyQuisinostat + doxorubicingARMSYesh,jIn vitro: Increased reduction cell viability and increased apoptosis(78)
Quisinostat + etoposideERMSIn vivo: Enhanced reduction tumor growth
Quisinostat + vincristine
Quisinostat + cyclophosphamide
Quisinostat + dactinomycin
HDAC + chemotherapyVorinostat + cisplatinERMSNoIncreased reduction cell viability and increased apoptosis(79)
Valproic acid + cisplatin
HDAC + multi-kinase or HSP90 or nucleoside reverse transcriptaseVorinostat + sorafenibERMSNoSorafenib: CI < 1.0 in ERMS (RD18) cell line(80)
Vorinostat + 17-DMAG17-DMAG/abacavir: CI > 1.0 in ERMS (RD18) cell line
Vorinostat + abacavir (Sorafenib + 17-DMAG)(Sorafenib + 17-DMAG: CI < 1.0 in ERMS (RD18) cell line)
HDAC + SMO or mTORC1 + COX2 or chemotherapyValproic acid + vismodegib (SMO) + AtorvastatinARMS PDXYeslEtinostat + docetaxel vs. etinostat: 65% tumor regression vs. 43% tumor regression(81)
Valproic acid + metformin (mTOR) + celecoxib (COX2)All other combination: PD
Entinostat + docetaxel
LSD + HDACGSK690 + QuisinostatARMSNoCI < 1.0 in ARMS (Rh30) and ERMS (RD) cell lines(82)
GSK690 + VorinostatERMS
Ex917 + Quisinostat
DNA methylationDNA demethylation + CTL activity5′ aza-2′-deoxtidine (DAC) + CTLARMS ERMSNoDAC increased sensitivity to CTL cytotoxicity(85)
  • Abbreviations: CI, combination index; CI < 1.0, synergism; CI = 1.0, additive effect; CI > 1.0, antagonism; IR, insulin receptor; IAPi, inhibitor of apoptosis protein inhibitor; N.A., not applicable; SN38, irinotecan active metabolite.

  • aPubChem ID available in Supplementary Table S1.

  • bCombination tested in vivo.

  • cOnly tested ERMS.

  • dZebrafish model.

  • eChicken embryo model.

  • fCompound not further specified.

  • gPubChem ID available in Supplementary Table S1.

  • hCombination tested in vivo.

  • iOnly tested ERMS.

  • jChicken embryo model.

  • kOnly ARMS.

  • lOnly in vivo examination.

  • mLiposome-protamine-siRNA particles specifically directed against PAX3-FOXO1 fusion.

  • nSubtype not specified.